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In sickness and in health – Gene therapy could revolutionise medicine,

By Nell Boyce

NEWSPAPERS in the US are carrying an advertisement for a company called Gattaca that can genetically engineer your offspring. “How far will you go?” it asks. “How far will your child go?” There follows a list of genetic traits that can be altered, such as skin colour, premature baldness, intellect, athletic prowess, stature, aggressive tendencies and musical abilities, as well as obesity, alcoholism and predisposition to disease.

The ad is a spoof designed to spark interest in a science fiction film of the same name that is released this week. But it makes no mention of the film, and many people have found the promotion unsettling. While the “modifications” that Gattaca offers are indeed science fiction, in real life the line between the treatment of disease and the “enhancement” of normal traits is becoming increasingly blurred.

Human growth hormone treatment, for example, was developed for people with an inherited hormone deficiency, but it is now also prescribed for short, healthy children to help them grow. And athletes can boost their performances by taking erythropoietin, a drug that stimulates the production of red blood cells and is usually used to treat anaemia.

There are fears that gene therapy will go the same way. Already, researchers are manipulating genes to treat more than just rare, devastating diseases. The world’s first gene therapy trial began in 1990, and since then scientists have carried out hundreds of trials on thousands of patients. But only a few dozen of them have involved diseases caused by defects in single genes. Most researchers are working on multi-gene disorders such as cancers, infectious diseases and nonfatal conditions such as arthritis. Characteristics such as appearance and personality are also determined by more than one gene, and some ethicists fear that multi-gene research will eventually lead to the genetic manipulation of these traits.

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Earlier this year, members of the Recombinant DNA Advisory Committee of the National Institutes of Health (NIH) near Washington DC approved the first gene therapy trial in healthy people. Ron Crystal of the University of Pittsburgh, Pennsylvania, will inject volunteers with a virus that carries a gene for cytosine deaminase, a therapy he has used in patients with colon cancer, to find out how a normal immune system responds to the virus. Although Crystal’s study is ultimately concerned with the treatment of disease, some members of the advisory committee were concerned that it “crossed the bridge” that has traditionally kept scientists from tinkering with the genetic code in healthy people.

The full treatment

To address these concerns, the committee held a public meeting last month so that scientists and ethicists could debate how to prevent genetic engineering that changes normal characteristics such as appearance, performance and personality. Eric Jungst of Case Western Reserve University in Cleveland, Ohio, an ethicist who serves on the committee, believes that companies will initially seek approval for enhancement gene therapies by disguising them as medical treatments. “Just about every enhancement we can think of could be packaged in a way that is treatment,” he says. For example, a therapy to improve memory might claim only to prevent Alzheimer’s disease.

Several scientists point out that ideas such as memory enhancement belong to science fiction, or the distant future. So far no gene therapy trial has shown any dramatic effect on patients, and no one knows enough about the genetics of normal human traits to have any hope of successfully tinkering with them. “Humans and great apes share 99 per cent of the same DNA, and we don’t understand the genetics behind their behavioural and morphological differences,” says Hunt Willard, also at Case Western Reserve University, who has developed artificial human chromosomes.

French Anderson, a gene therapy researcher at the University of Southern California in Los Angeles, says that geneticists understand the human genome about as well as the average person understands television—if a television set breaks, they may be able to reconnect a disconnected wire, but that does not mean that they know enough to improve the set’s picture or sound.

Other scientists disagree. They warn that in the next few years, government agencies might be asked to approve therapies that could be used to alter traits in healthy people. “There are certain areas where we could edge into enhancement very gently with existing technology,” notes Christopher Evans, a gene therapy researcher working on arthritis at the University of Pittsburgh School of Medicine. For example, companies have developed gene therapies for hereditary high cholesterol that could be used to prevent heart attacks in people without the genetic disorder.

The risks of altering genetic traits in healthy people are completely unknown. So far, no patients appear to have suffered ill effects in gene therapy trials, except for inflammatory responses to the viruses or other vectors used to transport the genes. No one knows if the added genes will trigger cancers or other diseases sometime in the future. But if the technology proves safe, then using genes for enhancement might seem little different from using the products of genes, such as human growth hormone or erythropoietin, in this way.

What sets gene therapy apart, however, is that inserted genes could find their way into sperm or egg cells and be passed on to children. If this occurred, the genetic change would exist in every cell of the body, rather than just the tissues targeted by researchers, and the change could affect future generations. While scientists have no evidence that a transferred gene has ever spread to sperm or eggs, they have no proof that it will not happen. “We’re relatively ignorant of the fate of transferred DNA,” says Willard.

The prospect of altering reproductive cells to engineer a child, as portrayed in Gattaca, makes most people uneasy. No scientist or company publicly advocates trying to cure disease by manipulating human sperm, eggs or recently fertilised eggs, and most condemn the idea of germ line enhancements. The NIH states flatly that it will not entertain any proposal for germline therapy because of the unknown risks to children, and some countries, including Germany, have banned such experiments.

Even so, germline alterations are made every day in the lab, albeit only to create transgenic mice and other animals. Scientists stress, however, that the technique is not nearly efficient enough to use in humans. “The only reason that transgenic mice are so feasible to do is that we can play the numbers game,” says Scott McIvor, director of the gene therapy programme at Minnesota University. “If you inject foreign DNA into 150 mouse fetuses and implant them into mice prepared for pregnancy, maybe 50 of the fetuses will survive and 5 will be transgenic.”

Technology trap

But Theodore Friedman of the University of California at San Diego, who wrote a seminal paper on gene therapy 20 years ago in Science, says that Dolly—the sheep cloned by researchers at the Roslin Institute near Edinburgh—proves that new technologies can quickly turn science fiction into fact. He believes that the NIH can no longer hide behind its dismissal of germline alterations. “I think you have to consider it, because it is going to come,” he says. “We’ll go first and foremost to obvious disease, but we will have the temptation to move to other traits very quickly.”

And Eric Parens, who heads an enhancement technology study group at The Hastings Center, a think-tank based in New York, points out&colon; “Technologies don’t come marked `for treatment’ or `for enhancement’. The same technology can be put to very different purposes. In practice, if we say yes to germline gene therapy, we are also saying yes to germline enhancement.”